Multilayered controlled release pharmaceutical dosage form

ABSTRACT

This invention is directed to a multilayered controlled release pharmaceutical dosage form. More particularly the dosage form is adapted for water soluble drugs and comprises a plurality of coated particles wherein each has multiple layers about a core containing a drug active whereby the drug containing core and at least one other layer of drug active is overcoated with a controlled release barrier layer and preferably an outer layer of additional drug is adapted for immediate release to preferably provide one immediate releasing layer and at least two controlled releasing layers of a water soluble drug from the multilayered coated particle.

This is a division of application Ser. No. 08/319,186, filed Oct. 6,1994, which is hereby incorporated by reference, U.S. Pat. No.5,474,786.

FIELD OF THE INVENTION

This invention is directed to a multilayered controlled releasepharmaceutical dosage form. More particularly, the dosage form isadapted for controlled release of water soluble drugs and comprises aplurality of multilayered coated particles, wherein each particle hasmultiple layers about a core containing a drug active. The drugcontaining core and at least one other layer of drug active isovercoated with a controlled release barrier layer and an outer layer ofadditional drug may be adapted for immediate release.

BACKGROUND OF THE INVENTION

Controlled release pharmaceutical dosage forms are well known andprovide distinct advantages for delivery of certain chemotherapies.Controlled release dosage forms are particularly useful for drugs whichact optimally at certain levels of plasma concentration over extendedperiods of time. Controlled release systems may also avoid the presenceof ineffective or toxic levels of drugs which result from periodicadministration of immediate release dosage forms which provide highinitial levels of drug but may leave only ineffectively small amounts ofdrugs in the plasma near the end of the administration periods (i.e.cycles) prior to subsequent administration of drug. Controlled releasedosage forms are also desirable for providing continuous chemotherapyfor chronic conditions or those with a long duration of therapy byproviding drugs in a sustained released manner that only requiresadministration either once or twice daily instead of every four to sixhours as may be indicated for a particular drug.

The administration of highly water soluble drugs in a controlled releasedosage form presents particular problems. The introduction of suchhighly water soluble drugs in controlled release dosage forms into apatient's digestive system has met with limited success due to thenormally unpredictable leaching out of the very water soluble drugactive into the digestive system when using conventional sustainedrelease techniques. It is also challenging to provide a substantiallyzero or constant rate of release for drugs that are highly water solublefor extended periods of time.

It is therefore an object of the present invention to provide amultilayered controlled release pharmaceutical dosage form system,particularly for very water soluble drugs. This system providesdesirable plasma levels of drugs with a substantially constant rate ofrelease of the drugs from controlled release layers over a preselectedperiod of time.

SUMMARY OF THE INVENTION

To achieve the objects and objectives in accordance with the inventionthe present invention provides a multilayered controlled releasepharmaceutical dosage form, preferably for water soluble drugs,comprising a plurality of coated particles each comprising: a drugactive core which is sequentially overcoated with a first controlledrelease barrier layer; at least one additional layer containing drugactive which is overcoated with an additional controlled release layer;and preferably an outer layer containing drug active which is intendedfor immediate release; whereby, the amount of drug active in thecontrolled release barrier material utilized in each coating layerthereof is provided in amounts effective to achieve a desirable plasmalevel of drug active in a patient over a preselected time period. Inparticularly preferred embodiments the time period is twelve ortwenty-four hours (i.e. corresponding to once or twice dailyadministration).

In preferred embodiments of the invention the multilayered controlledrelease pharmaceutical dosage form for water soluble drugs comprises aplurality of coated particles each comprising:

a core comprising an inert material which is coated or granulated with awater soluble drug active;

a first coating layer over the drug containing core comprising a watersoluble film forming polymer, preferably the film forming mixtureadditionally comprises a plasticizer;

a second coating layer over the first coating layer comprising a filmforming dispersion or solution which forms a controlled release layerover the coated drug core, preferably a water-based dispersion;

a third coating layer comprising a water soluble film forming polymerand preferably a plasticizer;

a fourth coating layer comprising additional water soluble drug active;

a fifth coating layer comprising a water soluble film forming polymerand preferably a plasticizer;

a sixth coating layer comprising a film forming dispersion or solutionwhich forms a controlled release layer over the coated drug core,preferably a water-based dispersion; and

a final coating layer of a water soluble film forming polymer andpreferably a plasticizer.

In preferred embodiments of the invention the water soluble film formingpolymer is hydroxypropyl methylcellulose and the plasticizer ispolyethylene glycol.

Preferably the film forming polymer which forms the controlled releaselayer is provided as a water-based dispersion and comprises ethylcellulose. Preferably the dispersion additionally comprises at least oneof dibutyl sebacate, oleic acid, and sodium lauryl sulfate.

In preferred embodiments of the invention the water soluble drug activeis selected from the group consisting of tramadol, pseudoephedrine andphenylpropanolamine and salts thereof. More preferably the drug activeis very water soluble and is tramadol HCl or pseudoephedrine HCl. Mostpreferably the drug active is tramadol HCl. The invention is alsointended to cover substantially pure active enamtiomers of these drugactives.

In a particularly preferred embodiment of the invention the controlledrelease layers of the second and sixth coating layers are provided atlevels to obtain a substantially constant release profile of the drugactive over about a twenty-four hour period.

In other embodiments the invention provides a method of achieving adesirable plasma level of a water soluble drug over a twenty-four hourperiod in a patient comprising the steps of:

preparing a multilayered controlled release dosage form by sequentiallyovercoating a drug active containing core with a first controlledrelease barrier layer;

providing at least one additional layer containing drug active over saidfirst controlled release barrier layer which in turn is overcoated by anadditional controlled release layer; and

providing an outer layer containing drug active which is intended forimmediate release; whereby, the amount of drug active and the controlledrelease barrier material utilized in each coating layer thereof isprovided in an amount effective to achieve a desirable plasma level ofdrug active in a patient over a twenty-four hour period.

In preferred embodiments of the method of the invention the drug istramadol HCl or pseudoephedrine HCl.

In other preferred embodiments of the method of the invention thesequential coatings are all applied in aqueous systems.

In particularly preferred embodiments of the method of the invention themultilayered dosage form comprises at least one additional coating layerof a water soluble film forming polymer interposed between one or moreof the controlled release layers and the adjoining layer containing drugactive to assure uniformity of the dosage form.

In other embodiments of the invention two or more drug actives may beprovided in one or more of the drug containing layers of themultilayered dosage forms.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a graph showing percent dissolved over time of single anddouble layer (controlled release layer) coated beads of the drugtramadol HCl.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

Reference will now be made in detail to preferred embodiments of theinvention. Examples of the preferred embodiments are illustrated in thefollowing example section.

As used herein the term water soluble refers to those compounds andcompositions which range from slightly soluble to very soluble in water.Actives which are moderately to highly water soluble are particularlypreferred for use in this invention because the multilayered approachtaken herein provides barriers to premature leaching of water solubleactives which may, in clinical use, undesirably speed up the rate ofrelease of such actives from conventional sustained release dosageforms. Examples of very or highly water soluble actives include tramadolHCl, pseudoephedrine HCl and phenylpropanolamine HCl.

The multilayered controlled release pharmaceutical dosage form of theinvention is well suited for water soluble and very water soluble drugs.The plurality of coating layers including at least two controlledrelease layers and various sealing layers provide a dosage form whichpermits effective and desirable controlled release of drug substancefrom a plurality of coated pellets in a dosage form by providing atleast two diffusion barriers through which drug active is slowlyreleased. The multilayered coated particles of the invention areparticularly well suited for very water soluble drugs since themulticontrol release barrier approach of the present invention mitigatesthe possibility of premature leaching out of very water soluble drugactive in aqueous systems such as the digestive tract. While the presentinvention can be used for non-water soluble drugs it is particularlyadvantageous when applied to more water soluble drugs which are moreprone to leaching as described above. The multilayered dosage form maycontain more than one drug active in any or all of the drug containinglayers thereof.

The drug active core of the multilayered controlled releasepharmaceutical dosage form is generally a sugar sphere which is coatedwith a drug active. This core may however be a combination of a drugactive and binder which is granulated into a sphere or the core may besome other non-active substance besides sugar. Each time drug active isprovided in a layer it is first overcoated with a water soluble filmforming polymer to inhibit the leaching of such drug active duringprocessing into the next applied layer, e.g. controlled release layer.Such leaching into the controlled release layer may have the effect ofcontaminating the controlled release layer to provide for inconsistentresults from layer to layer and/or batch to batch of the drug dosageform because the presence of the leached active would provide forpremature release of the active as well as opening up excess space inthe controlled release layer for further premature diffusion of the drugactive therefrom. The inclusion of such a protective layer over the drugactive is particularly indicated in the present invention because of theaqueous nature of the preferred water based polymer controlled releaselayer which is to be provided over each drug containing core. Further,in cases where the drug is particularly water soluble, undesirableleaching is a probable result absent provision of a protective coatingof a water soluble film forming polymer over the drug containing layer.

It is preferred that the water soluble film forming polymer comprises aplasticizer to assure adequate flexibility of the film forming polymerlayer. If the film forming polymer layer is comprised of a substancewhich inherently has adequate flexibility then a plasticizer may not benecessary. The water soluble film forming polymer is preferablyhydroxypropyl methylcellulose but may be other suitable polymers such ashydroxypropyl cellulose or povidone and more preferably additionallycomprises polyethylene glycol and or propylene glycol as plasticizer.Preferably this polymer is in a liquid solution. Other water solublepolymers may be applied as would be known to those skilled in the art.

The controlled release layer of the multilayered drug dosage form of theinvention is a diffusion layer through which drug is released in acontrolled manner. It is particularly desirable that the controlledrelease diffusion layer be water based for ease of processing andenvironmental concerns. The use of a water based dispersion to form acontrolled release layer indicates the use of a protective undercoatingas described above to protect against premature leaching of theunderlying drug into the subsequently applied controlled release layerwhich may provide inconsistent release patterns for the drug. While thepresent invention preferably provides for two controlled releasedlayers; three or more controlled release layers are contemplated and area part of the present invention. The use of two or more controlledrelease layers and the underlying drug layers may also provide forcustomization of the multilayered drug pellets controlled releaseprofile of one drug or for the release of a mixture of drug actives fromthe pellet.

In preferred embodiments of the invention an immediate release layer ofdrug is provided on the outside core of the multilayered pellet toprovide for the immediate introduction of an effective amount of drugactive to a patient. An effective level of drug active is thenmaintained through the gradual release of additional drug active bydiffusion through the controlled release layers of the drug while itremains in the digestive system.

The controlled release layer may be a solution or dispersion of a filmforming polymer. Preferably, the controlled release layer is applied asa water based dispersion comprising ethyl cellulose. More preferably,the dispersion additionally comprises plasticizer ingredients such asdibutyl sebacate and oleic acid. A particularly preferred water basedcontrolled release dispersion is sold under the trademark SURELEASE andcomprises ethyl cellulose, dibutyl sebacate, oleic acid, ammoniatedwater, and fused silica.

The multilayered controlled release pellets of the invention arepreferably provided in a hard gelatin capsule but may also be providedin any other suitable oral dosage form such as a matrix comprising suchpellets agglomerated with an appropriate and compatible binder to form aunitary solid dosage form which will release the intact pellets in thedigestive tract after swallowing.

The film forming process of the invention can be carried out inconventional pans, preferably pans with one way air flow to provide morecontrol over the pan environment. More preferably the coating isaccomplished in a fluidized bed which is an air suspension techniqueknown as "Wurster" coating. Most preferably the pellets are coated in arotor granulator with a top fluid bed which provides rotation of thepellets during coating to ensure a more uniform coat of the pellets.Examples of a preferred coating apparatus of the invention is a GLATTGPCG-5 rotor granulator. Other coating materials and techniques can beapplied such as those disclosed in The Theory and Practice of IndustrialPharmacy, Lachman et al., 3d edition, 1986.

The invention will now be illustrated by examples. The examples are notintended to be limiting of the scope of the present invention but readin conjunction with the detailed and general description above, providefurther understanding of the invention and outline a process forpreparing the compositions of the inventions and methods of practicingthe invention.

EXAMPLES

The following ingredients, processes and procedures for preparing thecompositions of the present invention correspond to that describedabove. The procedure below describes with particularity the variousformulation ingredients and procedures utilized. Any methods, startingmaterials, reagents or excipients which are not particularly describedwill be generally known and available to those skilled in thepharmaceutical formulation arts. All formulation percentages areprovided in percent by weight by total weight of the composition.

Example 1 300 mg. tramadol sustained release capsules

A. Composition: Unit Dose

The theoretical quantitative composition (per unit dose) for tramadolHCl 300 mg sustained release capsules is provided below:

    ______________________________________                                                        % weight/weight                                                                            mg/Capsule                                       Components      (theoretical)                                                                              (theoretical)                                    ______________________________________                                        Tramadol HCl    68.34        300                                              (OPADRY ® Clear                                                                           1.14         5.01                                             YS-3-7011).sup.1                                                              Purified Water, USP.sup.2                                                                     --           --                                               Sugar Spheres, NF                                                                             12.5         54.87                                            OPADRY ® Clear                                                                            4.48         19.66                                            YS-1-7006.sup.3                                                               SURELEASE ® E-7-7050.sup.4                                                                13.54        59.44                                            Capsules.sup.5  --           --                                               Total           100.00%      438.98 mg.sup.6                                  ______________________________________                                         .sup.1 A mixture of hydroxypropyl methylcellulose, polyethylene glycol an     propylene glycol.                                                             .sup.2 Purified Water, USP is evaporated during processing.                   .sup.3 A mixture of hydroxypropyl methylcellulose and polyethylene glycol     .sup.4 Solid content only of a 25% aqueous dispersion of a mixture of         ethyl cellulose, dibutyl sebacate, oleic acid, ammoniated water and fumed     silica. The water in the dispersion is evaporated during processing.          .sup.5 White, opaque, hard gelatin capsule, size 00.                          .sup.6 Each batch is assayed prior to filling and the capsule weight is       adjusted as required to attain 300 mg tramadol hydrochloride per capsule.

The quantitative batch composition for tramadol hydrochloride 300 mgsustained release capsule is shown below (Theoretical batch quantity25,741 capsules):

    ______________________________________                                        Components                 Weight                                             ______________________________________                                        Step 1: Preparation of Tramadol                                               Hydrochloride Beads (bead Build-up #1)                                                                   12.000                                             Opadry ® Clear YS-3-7011                                                                             0.200                                              Purified Water, USP        5.454                                              Sugar Spheres, NF          4.000                                              Total Weight Tramadol Hydrochloride                                                                      16.200  kg                                         Beads (Bead Build-up #1)                                                      Step 2: Clear & Sustained Release                                             Bead coating #1                                                               Tramadol Hydrochloride Beads                                                                             8.000                                              (derived from Step 1)                                                         Opadry ® Clear YS-1-7006                                                                             0.360                                              Purified Water, USP        5.928                                              Surelease ® E-7-7050   0.672                                              Total Weight Clear Coated Sustained                                                                      9.032   kg                                         Release Beads                                                                 Step 3: Tramadol Hydrochloride Beads                                          (Build-up #2)                                                                 Sustained Release Beads (derived from Step 2)                                                            8.000                                              Tramadol Hydrochloride     4.320                                              Opadry ® Clear YS-3-7011                                                                             O.072                                              Purified Water, USP        1.964                                              Total Weight Tramadol Hydrochloride                                                                      12.392  kg                                         Beads (Build-up #2)                                                           Step 4: Clear & Sustained Release Bead                                        Coating #2                                                                    Tramadol Hydrochloride Beads                                                  (derived from Step 3)      10.000                                             Opadry ® Clear YS-1-7006                                                                             0.250                                              Purified Water, USP        6.450                                              Surelease ® E-7-7050   1.050                                              Total Weigh Tramadol Hydrochloride                                                                       11.300  kg                                         Sustained Release Beads                                                       Step 5: Capsule Filling    --                                                 ______________________________________                                    

B. Methods of Manufacturing and Packaging

NOTE: The drug substance and excipients may be deagglomerated, ifneeded, by milling or screening.

Step 1: Preparation of Tramadol Hydrochloride Beads (Bead Build-up #1)

a. Preparation of Tramadol Hydrochloride Build-up Solution

i. Admix the batch quantity of Purified Water, USP and the batchquantity of Opadry® Clear YS-3-7011.

ii. Add the batch quantity of tramadol hydrochloride and mix forapproximately 1.5 hours.

b. Preparation of Tramadol Hydrochloride Beads

i. Load the bowl of a suitable bead coater such as the Glatt GPCG 5Rotor-Granulator with the batch quantity of sugar spheres, NF and heatuntil the bed reaches approximately 40° C.-60° C.

ii. While maintaining the bed temperature at approximately 40°-60° C.,spray the entire tramadol hydrochloride/Opadry® Clear YS-3-7011 solutionprepared in Step 1.a. onto the sugar spheres.

iii. Remove the tramadol hydrochloride beads from the granulator andscreen to remove any agglomerates and any fine powder.

Step 2: Clear and Sustained Release Bead Coating #1

a. Preparation of Clear Coat #1

Add 54.7% of the batch quantity of Purified Water, USP (3.240 kg) andthe batch quantity of Opadry® Clear YS-1-7006 (0.360 kg) and mix forapproximately 1-2 hours.

b. Preparation of Sustained Release Dispersion #1

Add 11.3% of the batch quantity of Purified Water, USP (0.672 kg) and2.688 kg of Surelease® E-7-7050 dispersion and mix for approximately 1-2hours.

c. Preparation of Coated Beads

i. Transfer the batch quantity of the tramadol hydrochloride beadsprepared in Step 1. (8.0 kg) into a suitable bead coater such as theGlatt GPCG 5 Rotor-Granulator and heat until the bed reachesapproximately 40° C.-60° C.

ii. Maintain the bed temperature at the following conditions and spray:

40° C.-60° C. 88.9% of the Opadry® Clear YS-1-7006 solution prepared inStep 2.a.

42° C.-50° C. the batch quantity of the Surelease® E-7-7050 dispersionprepared in Step 2.b.

40° C.-60° C. the remaining batch quantity (11.1%) of the Opadry® ClearYS-1-7006 solution prepared in Step 2.a.

iii. Remove the tramadol sustained release beads derived in Step 2.c.ii.from the granulator and screen the beads to remove any agglomerates andany remaining fine powder.

Step 3: Tramadol Hydrochloride Beads (Build-up #2)

a. Preparation of the Tramadol Hydrochloride Build-up Solution

i. Add the batch quantity of Purified Water, USP and the batch quantityof Opadry® Clear YS-3-7011.

ii. Add the batch quantity of tramadol hydrochloride and mix forapproximately 1-2 hours.

b. Preparation of the Tramadol Hydrochloride Beads

i. Load the bowl of a suitable bead coater such as the Glatt GPCG 5Rotor-Granulator with the batch quantity of sustained release beads fromStep 2. (8.0 kg) and heat until the bed reaches approximately 40° C.-60°C.

ii. Spray on the entire tramadol hydrochloride/Opadry® Clear YS-3-7011solution prepared in Step 3.a. onto the heated sustained release beads,while maintaining the bed temperature at approximately 40° C.-60° C.

iii. Remove the tramadol hydrochloride beads from the granulator andscreen the beads to remove any agglomerates and any fine powder.

Step 4: Clear and Sustained Release Bead Coating #2

a. Preparation of Clear Coat

Add 34.9% of the respective batch quantity of Purified Water, USP (2.250kg) and the respective batch quantity of Opadry® Clear YS-1-7006 (0.250kg) and mix for approximately 1-2 hours.

b. Preparation of Sustained Release Dispersion #2

Add to a suitable stainless steel mixing tank 16.3% of the batchquantity of Purified Water, USP (1.050 kg) and 4,200 kg of Surelease®E-7-7050 dispersion and mix for approximately 1-2 hours.

c. Preparation of Coated Beads

i. Transfer the batch quantity of the tramadol hydrochloride beadsprepared in Step 3. (10.0 kg) into a suitable granulator such as theGlatt GPCG 5 Rotor-Granulator and heat until the bed reachesapproximately 40° C.-60° C.

ii. Maintain the bed temperature at the following conditions and sprays:

40° C.-60° C. 80% of the Opadry® Clear YS-1-7006 solution prepared inStep 4.a.

42° C.-50° C. the batch quantity of the Surelease®E-7-7050 dispersionprepared in Step 4.b.

40° C.-60° C. the remaining batch quantity (20.0%) of the Opadry® ClearYS-1-7006 solution prepared in Step 4.a.

iii. Remove the tramadol sustained release beads derived in Step 4.c.ii.from the granulator and screen the beads to remove any agglomerates andany remaining fine powder.

iv. Dry the beads in a 45° C.-55° C. dry heat oven for approximately 24hours.

Step 5: Capsule Filing

a. Based on the in-process assay results, calculate the fill weight ofthe tramadol hydrochloride sustained release beads.

b. On a suitable filling machine or by hand, fill the calculated amountof tramadol hydrochloride sustained release beads into white, opaque,hard gelatin capsules (size 00).

Example 2 Preparation of Pseudophedrine sustained Release Capsules

Follow the procedure of Example 1 but replace the tramadol HCl withpseudophedrine HCl and reduce all of the ingredients to two-thirds toproduce 200 mg pseudophedrine sustained release capsules.

The present invention provides for a heretofore unrealized consistentdrug release pattern for very water soluble drugs such as tramadol HCland pseudophedrine HCl from a sustained released pellet system. Theadvantages obtained by the multilayered pellets of the invention areindicated in the appended graph of FIG. 1 for comparing formulations fortramadol. The graph shows that the double layer bead of the invention(i.e. two controlled release layers, i.e. 8% and 10% controlled releaselayer amounts, by weight of the total weight of the beads) provides amore linear (i.e., more constant or uniform) release rate as compared tosingle layered beads with a single controlled release layer (i.e., 12.5%and 14% controlled release layer amounts by weight of the total weightof the beads).

The scope of the present invention is not limited by the description,examples or suggested uses herein and modifications can be made withoutdeparting from the spirit of the invention. The multilayered dosageforms of the invention may, for example, have other applications anduses in addition to those described herein, e.g. for vitamin supplementsor for controlled delivery of diagnostic agents.

Applications of the compositions and methods of the present inventionfor medical or pharmaceutical uses can be accomplished by any clinical,medical, and pharmaceutical methods and techniques as are presently orprospectively known to those skilled in the art. Thus it is intendedthat the invention cover any modifications and variations of thisinvention provided that they come within the scope of the appendedclaims and their equivalents.

What is claimed is:
 1. A multilayered controlled release pharmaceuticaldosage form for water soluble drugs comprising a plurality of coatedparticles each comprising: a drug active core comprising a mixture ofhydroxypropyl methylcellulose, polyethylene glycol and propylene glycolwhich is sequentially overcoated with a first controlled release barrierlayer comprising ethyl cellulose; and at least one additional layercontaining drug active comprising a mixture of hydroxypropylmethylcellulose, polyethylene glycol and propylene glycol which isovercoated with an additional controlled release layer comprising ethylcellulose; whereby, the amount of drug active and the controlled releasebarrier material utilized in each coating layer thereof is provided inamounts effective to achieve a desirable plasma level of drug active ina patient over a preselected twelve to twenty-four hour period.
 2. Themultilayer dosage form of claim 1 additionally comprising an outer layercontaining drug active which is intended for immediate release.
 3. Themultilayer dosage form of claim 1 comprising at least one additionalcoating layer of a water soluble film forming polymer interposed betweenone or more of the controlled release layers and the adjoining layercontaining drug active.
 4. A method of achieving a desired plasma levelof a water soluble drug over a desired time period in a patientcomprising the steps of:preparing a multilayered controlled releasedosage form by sequentially overcoating a drug active containing corecomprising a mixture of hydroxypropyl methylcellulose, polyethyleneglycol and propylene glycol with a first controlled release barrierlayer comprising ethyl cellulose; and providing at least one additionallayer containing drug active comprising a mixture of hydroxypropylmethylcellulose, polyethylene glycol and propylene glycol over saidfirst controlled release barrier layer which is overcoated by anadditional controlled release layer comprising ethyl cellulose; whereby,the amount of drug active and the controlled release barrier materialutilized in each coating layer thereof is provided in an amounteffective to achieve a desirable plasma level of drug active in apatient over a desired period of time.
 5. The method of claim 4additionally comprising an outer layer containing drug active which isintended for immediate release.
 6. The method of claim 4 wherein thedesired time period is about twelve or twenty-four hours.
 7. The methodof claim 4 wherein the drug is tramadol HCl or pseudoephedrine HCl. 8.The method of claim 4 wherein the sequential coatings are all applied inaqueous systems.
 9. The method of claim 4 wherein the multilayereddosage form comprises at least one additional coating layer of a watersoluble film forming polymer interposed between one or more of thecontrolled release layers and the adjoining layer containing drugactive.
 10. The method of claim 4 wherein two or more different drugactives are provided in the dosage form.